Alpha - hydrocarbon - beta polyiobo



United States Patent Ofilice 3,119,859 Patented .Fan. 28, 1964 Thepresent invention relates to X-ray contrast agents or roentgenographiccontrast agents, to the use thereof and to the production thereof.

This application is a continuation-in-part of our copending applicationSerial No. 803,359, filed April 1, 1959, for TrisubstitutedFormamidines, now abandoned.

It is an object of the present invention to provide new X-ray contrastagents and methods of producing the same.

It is a further object of the present invention to provide X-raycontrast agents which are particularly suitable for peroral applicationand which have a markedly good resorbability.

It is another object of the present invention to provide X-ray contrastagents which have an improved distribution in the gall blader and whichgive marked shadows for X-ray purposes.

It is still another object of the present invention to provide for theproduction of the new contrast agents of the present invention andmethods of producing the same.

Other objects and advantages of the present invention will be apparentfrom a further reading of the specification and of the appended claims.

With the above objects in view, the present invention mainly comprises acompound selected from the group consisting of compounds having thefollowing general formula:

OH2-([] HC O O H (1) R wherein R is selected from the group consistingof hydrogen, alkyl of 1-6 carbon atoms and cycloalkyl of up to 6 carbonatoms, wherein R and R are each selected from the group consisting oflower alkyl of 1-6 carbon atoms, and together with the N-atom 5 and 6member heterocyclic rings, and wherein nis a whole number from 2-3,non-toxic, physiologically compatible salts thereof, and compoundshaving the following general formula:

wherein R, R R and n have the same definitions as above and wherein R isselected from the group consisting of alkyl of 1-6 carbon atoms andcycloalkyl of up to 6 carbon atoms.

The X-ray contrast agents of the present invention may be prepared byreacting the known iodinated amino-phenyl-propionic acid, acid additionsalt or ester with the chosen N-dialkylated formarnide with an acidreaction aiding agent such as phosphorous oxychloride. Other methods canof course be used instead. Obviously in the case of producing the saltsthe reaction may be carried out with the N-dialkylated formamide and theamino-isodophenyl-propionic acid in the form of the free acid and thenreaction with a non-toxic, physiologically compatible base to form thesalt. Likewise, reaction can be carried out with the free acid andesterification can be subsequently carried out to produce the carboxylicacid esters of the present invention.

The reaction actually proceeds in accordance with the followingequation:

wherein R, R R and n have the same definitions as above, and wherein Xis an acid aiding agent. Among the particularly suitable acid reactionaiding agents X may be mentioned the halogenides of oxygen acids ofphosphorus and sulfur such as phosphorus trichloride, phosphorusoxychloride, thionyl chloride, sulfuryl chloride, chlorosulfonic acid,halogenides of organic sulfonic acids, such as benzenesulfonyl chloride,or carbonic acid halogenides such as phosgene and even acetyl chloride,benzoyl chloride and the like. In addition, the so called ansolvo acids(see Liebigs Annals, 455, 227 (1927)) such as hydrogen chloride adductsof zinc chloride, etc. These reaction aiding agents correspond to acertain degree to the acidic condensation agents which are used in theVilsmair aldehyde synthesis, which synthesis can to some extent becompared with the synthesis of the present invention. (Note Houben-Weil,Methoden der organischen Chemie, 1954, volume 7, pages 2936.)

The method of the present invention is an exothermic reaction whichproceeds extremely smoothly and with good yields. The reaction isgenerally carried out by first bringing together the chosen primaryamine or its acid salt, preferably its chlorohydrate, preferably with anexcess of the chosen N-disubstituted formarnide, which simultaneouslyserves instead of or in addition to an inert further solvent, and thechosen icondensation agent is then added slowly to the mixture,preferably while maintaining the temperature at approximately 50-60" C.In order to maintain the temperature it may be necessary to utilize acooling mediurn. The condensation agent is preferably utilized insubstantially equimolar quantities with respect to the utilized primaryamine. In View of the great variety of possible suitable condensationagents the possibility exists according to the present invention tochoose the condensation agent which gives the optimum results with theparticular reactants which are utilized in any particular case. However,it should be strongly noted that even when the typical N-acylationagents such as benzene sulfonyl chloride, benzoyl chloride or phosgene,the expected N-acylation of the utilized primary amine often does notoccur, but is instead pushed aside for the preferable amidinationreaction of the present invention.

In the above formulas R and R may be the same or different lower alkylor cycloalkyl radicals such as methyl, ethyl, n-propyl, isopropyl,butyl, hexyl, cyclopentyl, cyclohexyl or the like, or R and R togetherwith the nitrogen atom to which they are attached may form aheterocyclic ring radical such as piperidyl, morpholinyl, pyrazolyl,pyrrolidyl, piperazyl, or the like. The substituent R may be hydrogen, alower alkyl of up to 6 carbon atoms such as methyl, ethyl or the like,or a cycloalkyl of up to 6 carbon atoms.

The substituent R, which may be introduced into the molecule of theX-ray contrast agents of the present invention either before or afterthe reaction with the N dialkylated formamide, may likewise be a loweralkyl or a cycloalkyl of up to 6 carbon atoms.

The above set forth esters of the present invention may be used, thefree acids may be used or their non-toxic salts with organic orinorganic bases, particularly those which have a very low toxicity.Among the suitable non-toxic salts of the present invention are salts ofnontoxic inorganic bases such as alkali metal salts, e.g., sodium,lithium, etc., ammonium salts, alkaline earth salts such as calciumsalts, and salts of non-toxic organic bases such as glucosamine,methyl-glucosamine, ethanolamine, diethanolamine, glucamine,methylglucamine, ethylamine, diethylamine, etc. among many, many others.These salts are given for illustrative purposes only and it is apparentthat the present invention is applicable to all commonly usedphysiologically compatible salts.

The following examples are given as illustrative of the production ofthe new compounds of the present invention. It is to be understood thatthese examples are only given with respect to the production of acertain few selected compounds but that other compounds within thegeneral formula given above may be produced analogously to thosecompounds set forth in these examples. The scope of the invention isnot, therefore, meant to be limited to the specific details of theseexamples.

EXAMPLE 1 25 g. of a-ethyl-fi-(3-amino-2,4,6-triiodophenyl)-propionicacid are dissolved in 25 cc. of dimethyltormarnide and 6.72 g. ofphosphorous oxychloride are added thereto dropwise under stirring. Thestrong exothermic reaction mixture is immersed in an ice water bath tomaintain the reaction temperature at 55 C. After completion of thedropwise addition the reaction mixture is heated for an additional 1hour at a temperature of 55 C. This results in the beginning of aprecipitation of a white precipitate of the honey-like reactionmaterial. After cooling, the reaction mass is taken up in acetone, theprecipitated chlorohydrate of the amidine is filtered off by suction,washed with acetone and dried. The chlorohydrate is dissolved in hotwater at a temperature of 60 C., filtered, cooled to room temperature,and the solution is mixed with aqueous sodium hydroxide to a pH of 6resulting in the precipitation of the inner salt of methyl-,6-

(3 dimethylaminomethyleneamino 2,4,6 triiodophenyl)-propionic acid. Upondrying in air the substance contains approximately 1% of Water anddecomposes at about 75 C. without a characteristic melting point. Theyield is 24 g. (87% of the theoretical).

17 g. of et-methyl-fi-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl -propionic acid having a melting point of 120-122 C.(under decomposition) are produced in an analogous manner from 27.8 g.of ot-methyl-fi-(3-amino-2,4,6-triiodophenyl)-propionic acid, thereaction product being precipitated from ether-petroleum ether. Theyield corresponds to 56% of the theoretical.

EXAMPLE 2 1100 g. of B-(3-arnino-2,4,6-triiodophenyl)-propionic acid aredissolved in a mixture of 2470 cc. of dimethylformamide and 1235 cc. ofchloroform. A mixture of 312 g. of phosphoroxychloride and 450 cc. ofchloroform are added dropwise under stirring at a temperature of 0 to C.After the end of the addition the reaction mixture is stirred for anadditional three hours at room temperature and the separated reactionproduct is then filtered off by suction and washed with chloroform andacetone. By dissolving this reaction product in 5 liters of water withsodium hydroxide to a pH of 8 and the pH is then adjusted with dilutehydrochloric acid to a pH of 5.5 resulting in precipitation. Theprecipitate is filtered off by suction and recrystallized from ethanoland then dried in air. There is thus obtained 1000 g. of ti (3dimethylaminomethylene-amino-2,4,6-triiodophenyl)-propionic acid havinga melting point of 168l69 C. The yield corresponds to 82.5% of thetheoretical.

The advantages of the new X-ray contrast agents of the present inventionare evident particularly by a very low toxicity, a markedly goodresorbability upon peroral application and a considerably better gallbladder distribution with simultaneously better contrast transmission.Consequently the new compounds of the present invention are particularlyuseful as shadow-giving substances in Y-ray contrast compositions forperoral cholecystography. By suitable working up the compounds of thepresent invention are also usable as roentgenographic agents for otherbody portions or organs. Depending upon the particular purpose for whichthe compounds is 0t be used the compound may be used as their free acid,as their non-toxic salts with inorganic or organic bases, or as theiresters. For peroral oholecystography the compounds may be worked up intothe form of dragees, or the like.

The advantages of the new compounds of the present invention is evidentupon comparison thereof with already known contrast agents in aminaltests. By comparison of the present invention compound (I) (It-ethyl- B(3 dimethylamino methylamino 2,4,6 triiodophenyl)-propionic acid withthe corresponding known i.v.=intraveuous. i.d.:i.ntrrduodenal. p.o.=per0s.

By comparison of the present invention compound (III) ,8 (3dimethylamino methylenearnino 2,4,6- triiodophenyl)-propionic acid andthe present invention compound (I) a ethyl B (3 dimethylaminomethyleneamino-2,4,6-triiodophenyl)-propionic acid with the knowncompound (IV) ,8-(3-amino-2,4,6-triiodophenyl)- propionic acid, thefollowing values are obtained:

Table 2 Gall distribution in percent after iutraduoilcnnl admin- LDsq,istration of lug/kg. in

i.v., rats, utter rug/kg.

1 Hour 3 Hours 4 Hours Further comparison of the known compound (II) aethyl ,8 (3 amino 2,4,6 triiodophenyl) propionic acid with the presentinvention compounds (V) a ethyl ,8 (3 N diethylamino methyleneamino-2,4,6 triiodophenyl) propionic acid, (VI) 0: ethyl- [3 (3 N piperidinomethyleneamino 2,4,6 triiodophenyl)-propionic acid, and (VII) a-ethyl--(3-N-morpholino methyleneamino 2,4,6 triiodophenyl) propionic acid givethe following values:

Table 3 Gall distribution in 113 percent, after 100 mg./

kg. intraduodenal in awake (logs i.v., .o., In the gall In the rug/krug/kg urine 320 2, 500 11.1 3.8 148 l, 500 42. 4. 8 200 2, 000 43. O 7.4 305 l, 500 22.0 12.0

Table 4 Gall distribution in percent LD after administration of 100i.v., rug/kg. in rats, after mg/kg.

1 Hour 2 Hours 1 3 Hours It will be noted that although compound (VIII)has a higher toxicity than compound (X), the absolute value of thetoxicity of compound (VIII) of the present invention is still extremelygood and most important the gall distribution of compound (VIII) of thepresent invention is far better than that of compound (X). Furthermore,the toxicity of compound (X) as given in the table is somewhatdeceiving. Compound (X) when given in peroral heating of ratsprecipitates in the gall as thick white crystalline precipitate and as aresult obstructs the bile duct. Consequently compound (X) is absolutelyunsuitable as an oral X-ray contrast agent. Still further, since the1.13 of the still living 50% of the test animals is given after 3 days,the bile duct clogging caused by compound (X) which causes illness anddeath in the test animals only after the 3 days is not measured in theusual toxicity tests. Most important, none of thesedisadvantages ofcompound (X) occur with the compounds of the present invention.

The esters of the present invention are also extremely useful compoundshaving particular advantages. Thus, the esters in comparison to theknown nucleous-iodinated fl-(arnino-phenyl)-propionic acid have at leastthe same activity and in many respects the compounds of the presentinvention have superior and increased activity. A further particularadvantage of these compounds is in the fact that they are practicallycompletely tasteless while the known compounds, particularly theirsalts, in general have a very unpleasant bitter taste which makes itnecessary to use capsules or dragees for peroral application.

The surprisingly good resorbability of the esters of the presentinvention upon peroral application is evidenced by animal tests. Thus,in the case of an awake dog to which 100 rug/kg. of)8-(3-dimethylamino-methylene amino-2,4,6-triiodophenyl)-propionicacid-methylester has been administered perorally 33.5% separates throughthe gall. Under the same conditions 37.6% of 9 (3 dimethylaminomethyleneamino 2,4,6 triiodophenyl)-propionic acid-ethyl ester separatesthrough the gall while, for example, upon application of (3-(3-amino-2,4,6-triiodophenyl)-propionic acid-ethyl ester practically noresorption occurs.

Still better results are obtained with respect to the resorption ratioin the case of humans which upon peroral administration of 1.0 g. of,6-(3-dimethylarninon1ethyleneamino-2,4,d-triiodophenyl) -propionicacid-methyl ester after 24 hours show 83% separation. The correspondingvalues for the fl-(3-dimethylamine-methyleneamino-2,4,6-triiodophenyl)-propionic acid-ethyl ester is 70%, whereby the separationwas determined based upon the known reresorption, always in the 24 hoururine.

The esters of the present invention also show marked superiority withrespect to the toxicity thereof in comparison to the known substanceswhich are used for peroral cholecystography. Thus, the LD upon peroraladministration of /3-(3-dimethylamino-methyleneammo- 2,4,6triiodophenyl)-propionic acid-methyl ester is 10 g./ kg. in rats, thecorresponding value for /3-(3-dimethylamino-methyleneamino 2,4,6triiodophenyl)-propionic acid-ethyl ester is 4 g./kg., for[3-(3-rnorpholino-methyleneamino-2,4,-triiodophenyl)-propionicacid-ethyl esterchlorohydrate and forfi-(3-N-piperidino-rnethyleneamino- 2,4,6-triiodophenyl)-propionicacid-ethyl ester-chlorohydrate is 8 g./l g.

The esters of the present invention may be used either in the form offree esters or in the form of their acid addition salts with non-toxicinorganic and/or organic acids. All common inorganic and organic acidswhich are used for this purpose, for example hydrochloric acid,phosphoric acid, tartaric acid, etc. may be used for this purpose.

Further animal tests on awake dogs to which were perorally administeredmg./ kg. of various compounds showed that the present invention compounda-ethyl-p- (3-N-morpholino-methyleneamino 2,4,6 triiodophenyl)-propionicacid-ethyl ester-chlorohydrate resulted in a 7.7% separation through thegall while under the same conditions the administrations of the presentinvention compound a-methyl-B- 3-N-morpholino-methyleneamino-2,4,6-triiodophenyl)-propionic acid-ethyl ester-chlorohydrate resultedin a 22.8% separation through the gall.

Further toxicity test on rats comparing compounds of the presentinvention with known peroral cholecystography compounds showed that theLD upon peroral administration of the present invention compoundu-ethyl- ,B-(N-morpholino methyleneamino 2,4,6 triiodophenyl)-propionicacid-ethyl ester chlorohydrate is 8 g./kg. and this very surprisinglylow toxicity is the same for a-ethyl-fi-(3-N-piperidino-methyleneamino2,4,6 triiodophenyl)-propionic acid-ethyl ester-chlorohydrate, foru-methyhfi-(3-N-piperidino-methyleneamino 2,4,6 triiodophenyl)-propionic acid-ethyl ester-chlorohydrate,- fora-ethyl-B-(3-N-piperidino methyleneamino 2,4,6 triiodophenyl)-propionicacid-ethyl ester-chlorohydrate, and for a-e'thyl ,8(3-dimethylarninc-methyleneamino-Z,4,6- triiodophenyl)-propionicacid-ethyl ester-chlorohydrate.

The following examples are given to illustrate various X-ray contrastcompositions in accordance with the pres ent invention. The scope of theinvention is not, however, meant to be limited to the specific examples.

EXAMPLE 3 5 kg. of u-methyl-fi-(3-dimethylaminomethyleneamino-2,4,6-triiodophenyl)-propionic acid is kneaded with 2 liters of starchpaste containing 100 g. of corn starch, a kneading machine being usedfor this purpose. The wet mass is granulated in the usual manner in agranulation machine and dried under vacuum. The finished granulate isthen mixed with 0.5 kg. of corn starch and 25 g. of magnesium stearateand pressed into tablets each containing 500 mg. of the activeingredients.

7 EXAMPLE 4 The very water-soluble sodium salt of a-methyl-B-(3-dimethylaminomethyleneamino 2,4,6 triiodophenyD- propionic acid areintroduced into gelatin capsules. Each capsule contains 750 mg. of theactive ingredients. For machine filling of the capsules the sodium saltcan be worked up with 40% of paraffin oil to a flowable paste.

EXAMPLE 5 The granulate obtained according to Example 3 is formed intodragees by the application of 20% of its weight of sugar syrup in adragee-forming vessel, and the dragees are subsequently waxed.

EXAMPLE 6 1.25 kg. of [3-(3-dimethylaminomethyleneamino-2,4,6-triiodopbenyl)-propionic acid are kneaded with 0.5 liter of starch pastewhich contains 25 g. of corn starch, the kneading taking place in akneading machine. The wet mass is granulated in a granulation machine inthe usual manner and dried under vacuum. The finished granulate is thenmixed with 0.125 kg. of corn starch and 6 g. of magnesium stearate andpressed into tablets each of which contains 500 mg. of the activesubstance.

EXAMPLE 7 The very water-soluble sodium salt offl-(Z-dimethyiaminomethyleneamino 2,4,6 triiodophenyD-propionic acid isintroduced into gelatin capsules. Each capsule contains 750 mg. of theactive ingredient. For machine filling of the capsules the sodium saltcan be Worked up with 40% parai'fin oil to a flowable paste.

EXAMPLE 8 The granulate produced according to Example 6 is Worked upinto dragees along with 20% by Weight thereof of sugar syprup, thedragees subsequently being waxed.

EXAMPLE 9 3 g. of13-(3-dimethylamino-methyleneamino-2,4,6-triiodophenyl)-propionicacid-calcium salt, 2.5 g. of sugar, 25 mg. of sodium lauryl sulfonate,200 mg. of sodium carboxymethyl cellulose and 25 mg. of a tastecorrecting substance are thoroughly mixed and after shaking with 25 cc.of water can be easily ingested.

EXAMPLE 10 5 kg. of methyl-B-(3-N-diethylaminomethyleneamino-2,4,6-triiodophenyl)-propionic acid are kneaded with 2 liters of starchpaste containing 100 g. of corn starch, a

kneading machine being used for this purpose. The wet mass is granulatedin the usual manner in a granulation machine and dried under vacuum. Thefinished granulate is then mixed with 0.5 kg. of corn starch and 25 g.of magnesium stearate and pressed into tablets each containing 500 mg.of the active ingredients.

EXAMPLE 11 The very water-soluble sodium salt of rx-EthYlfi-(3N-piperidino methyleneamino-2,4,6-Iriiod0phenyl)-propionic acid areintroduced into gelatin capsules. Each capsule contains 750 mg. of theactive ingredient. For machine filling of the capsule the sodium saltcan be worked up with 40% of paraflin oil to a flowable paste.

EXAMPLE 12 The granulate obtained according to Example 10 is formed intodragecs by the application of of its weight of sugar syrup in adragee-forming vessel, and the dragees are subsequently waxed.

EXAMPLE 13 1.25 kg. of ;8-(3 N-piperidinc-methyleneamino-2,4,6-triiodophenyl)-propionic acid are kneaded with 0.5 liter of starch pastewhich contains g. of corn starch, the kneading taking place in akneading machine. The wet mass is granulated in a granulation machine inthe usual manner and dried under vacuum. The finished granulate is thenmixed with 0.125 kg. 01 corn starch and 6k. of magnesium stearate andpressed into tablets each of which contain 500 mg. of the activesubstance.

EXAMPLE 14 The very water-soluble sodium salt of ,B-(3-N-morpholinomethylenearnino 2,4,6-triiodophenyl)-propionic acid is introduced intogelatin capsules. Each capsule contains 750 mg. of the activeingredients. For machine filiing of the capsule the sodium salt can beworked up with 40% parafiin oil to a fiowable paste.

EXAMPLE 15 The granulate produced according to Example 13 is worked upinto dragees along with 20% by Weight thereof of sugar syrup, thesedragees subsequently being waxed.

EXAMPLE 16 5 kg. of[5-(3-dimethylamino-methyleneamino-2,4,6-triiodophenyD-propionicacid-methyl ester are kneaded with 2 liters starch paste containing g.of corn starch, a kneading machine being used for this purpose. The wetmass is granulated in the usual manner in a granulation machine anddried under vacuum. The finished granulate is then mixed with 0.5 kg. ofcorn starch and 6 g. of magnesium stearate and pressed into tablets eachcontaining 500 mg. of the active ingredient.

EXAMPLE 17 The granulate obtained by treating the 5 kg. of B-(3 Nmorpholino methyleneamino-2,4,6-triiodophenyl)- propionic acid-ethylester-chlorohydrate as in Example 16 is formed into dragces by theapplication of 20% of its weight of sugar syrup in a dragee formingvessel, and the dragees are subsequently waxed.

EXAMPLE 18 The granulate obtained by treating 5 kg. of tit-methyl- 5 (3dimethylamino-methyleneamino-2,4,6-triiodophenyl)-propionic acid-methylester is worked up into dragees along 20% by weight thereof of sugarsyrup, in a dragceforming vessel, and the dragees are subsequentlywaxed.

EXAMPLE 20 The sodium salt of m-hexyl-B-(3-dipropylaminomethyl-'eneamino-2,4,6-triiodophenyl)-propionic acid is filled into gelatincapsules. Each capsule contains 700 mg. of the active ingredient. Formachine filling of capsules the sodium salt can be worked up with 40%paraffin oil to a fiowable paste.

EXAMPLE 21 2.5 kg. offi(3-dihexylamino-methyleneamino-Z,4,6-triiodophenyl)-propionic acidwith 1 liter of starch paste which contains 50 g. of corn starch arekneaded in a kneading machine. After the granulation of the wet mass ina granulation machine it is dried under vacuum, mixed with 0.25 kg. ofcorn starch and 12 g. of magnesium stearate and pressed into tabletseach of which contain 500 mg. of the active ingredient.

EXAMPLE 22 The granulate which is obtained by treating 5 kg. of abutyl-({3-3-pyrrolidino-mcthyleneamino-diiodophenyl)- propionicacid-ethyl ester as described in Example 21 are formed into dragees in adragee-fonning vessel using 20% of its weight of sugar syrup, and thedragees are subsequently waxed.

EXAMPLE 23 The sodium salt ofa-propyl-B-(3-dihexyl-aminomethyleneamino-2,4,6-triiodophenyl)-propionicacid is Worked up in the same manner as the sodium salt ofa-hexyl-B-(3-dipropylamino-methyleneamino 2,4,6 triiodophenyl)-propionicacid in Example 20. The methylglucamine salts of the compounds ofExample 20 or 23 can be used instead of the sodium salt in the same manner.

EXAMPLE 24 1000 g. of B-(3-dimethylaminomethylene-aminc-2,4,-triiodophenyl)-propionic acid, produced according to Example 2 aresuspended in 2000 cc. of Water and then adjusted with the equivalent ofsodium hydroxide to a pH of 7. The solution thus obtained is filteredand mixed with 25 liters of acetone, resulting in the precipitation ofthe sodium salt of{3-(3-dimethylaminomethylene-amino-2,4,6-triiodophenyl)-propionic acid.The precipitate is filtered off by suction, suspended in 2000 cc. ofacetone, filtered again by suction and dried at 100 C. There is thusobtained 1000 g. of the sodium salt having a melting point of 303-304 C.(under decomposition). The yield corresponds to 95.5% of thetheoretical.

EXAMPLE 25 50 g. of {3-(3-dimethylaminomethylene-amino 2,4,6-triiodophenyl)-propionic acid, produced according to Example 2 aresuspended in 300 cc. of ethanol. After addition of 7.5 cc. of sulfuricacid the m xture is heated under reflux, resulting a clear solution.This solution was cooled and filtered, the precipitate dissolved in 320cc. ethanol and the solution, thus obtained upon slight warmin is addeddropwise under stirring and cooling into 600 cc. aqueous sodiumhydroxide. After several hours of continuous st rring the precipitate isfiltered off by suction and recrystallized from ethanol. There is thusobtained 37 g. of ethyl5-(3-dirnethylaminornethyleneamino-2,4,6-triiodophenyl)-propionatehaving a melting point of 72. The yield corresponds to 75% of thetheoretical.

EXAMPLE 26 25 g. of a-ethyl-fi-(3-amino-2,4,6-triiodophenyl)-propionicacid are dissolved in 50 cc. N-formyl-morpholine and 4.0 cc. ofphosphorous oxychloride are added thereto dropwise under stirring. Thestrong exothermic reaction mixture is immersed in an ice water bath tomaintain the reaction temperature at 60 C. After completion of thedropwise addition the reaction mixture is heated for additional 30minutes at a temperature of 60 C. This results in partialsolidification. After cooling, the reaction mixture is suspended inacetone and filtered by suction. The precipitate, thus obtained, isdissolved in dilute ammonium hydroxide and the solution is mixed withaqueous acetic acid to a pH of 4 resulting in the precipitation of theinner salt ofu-ethyl-fi-(S-N-morphol-inomcthylcne-amino-2,4,6-triiodophenyl)propionic acid. Upon drying in air the substance contains approximately1% of Water and decomposes at about 85 C. without a characteristicmelting point. The yield is g. (68% of the theoretical) 20 g. of thisacid are dissolved in 100 cc. of ethanol. After addition of 5 cc.sulfuric acid the mixture is heated under reflux for a period of 3hours. The solution thus obtained is poured into ice-water, madestrongly alkaline by addition of 50 cc. 40% aqueous sodium hydroxidesolution and extracted with diethyl ether. The extracts are washed withWater, dried with anhydrous sodium sulfate and the ether removed bydistillation. Crude ethyl ot-ethyl- ,8-(3-N-morpholinomethylene-amino2,4,6-triiodopheny1-)-propionate is obtained as a yellow oil, which donot solidify on standing. This product is dissolved in dry diethyl etherand the solution is mixed with a slight excess of ethanolic hydrochloricacid, resulting in the precipitation of the hydrochloric addition saltof ethyl aethyl-fi-(3-N-morpholinomethylene-amino2,4,6-triiodophenyl)-propionate, having a melting point of 210-211 C.(under decomposition). The yield (17 g.) corresponds to 78% of thetheoretical.

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can be applying current knowledgereadily adapted it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention and,therefore, such adaptations should and are intended to be comprehendedWithin the meaning and range of equivalence of the following claims.

What is claimed as new and desired to be secured by Letters Patent is:

1. A compound selected from the group consisting of compounds of theformula:

wherein R, R and R and n have the same definitions as above and whereinR is selected from the group consisting of alkyl of 1-6 carbon atoms andcycloalkyl of up to 6 carbon atoms; and non-toxic acid addition saltsthereof.

2. A com Jound of the formula:

wherein R is hydrogen, wherein R is lower alkyl, where in R is loweralkyl and wherein n is 3.

3. A compound of the formula:

wherein R is lower alkyl, wherein R is lower alkyl, wherein R is loweralkyl and wherein n is 3.

4. A compound of the formula:

/Ri N=CHN -oHioH--o o 0 R 11 wherein R is hydrogen, wherein R is loweralkyl, wherein R is lower alkyl, wherein R is lower alkyl and wherein nis 3.

5. A compound of the formula:

wherein R is lower alkyl, wherein R is lower alkyl, wherein R is loweralkyl, wherein R is lower alkyl and wherein n is 3.

6. fl-(3-dimethylamino-methylenearnino-2,4,6 triiodophenyl)-propionicacid.

7. The sodium salt offl-(3-dimethylamino-methyleneamino-2,4,6-triiodophenyl) -propionic acid.

8. The calcium salt ofp3-(3-dimethylamino-methyleneamino-2,4,6-triiodophenyl)-propionic acid.

9. ,6-(3-dimethylamino-methyleneamino-2,4,6 triiodophenyD-propionicacid-ethyl ester.

10. a-Methyl-B-(3-dimetl1ylamino-methyleneamino 2, 4,6-triiodophenyl)-propionic acid.

12 ll. a-Elhyl-B-(3-dimethylamino'methylenamino 2,4,6-triiodophenyl)-propionic acid.

12. A compound of the formula:

R1 N=CH-N CIIz-C|)H-C o 011 (1).. R

wherein R is cycloalkyl of up to 6 carbon atoms, wherein R is loweralkyl, wherein R is lower alkyl and wherein n is 3.

13. A compound of the formula:

wherein R is cycloalkyl of up to 6 carbon atoms, wherein R is loweralkyl, wherein R is lower alkyl, wherein R is lower alkyl and wherein nis 3.

No references cited.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA
 4. A COMPOUND OF THE FORMULA: